Duchenne Muscular Dystrophy

Figure Caption: Differentiating SCs (~100,000 cells) harvested from PET reporter-transgenic mice are detectable following transplantation into the right gastrocnemius muscle (GM) of an mdx dystrophic mouse. In contrast, SCs harvested from mice that lack the transgene (implanted into the left GM) are not visualized.
Future Directions

Assessing the efficacy of therapy for DMD is hampered by an inability of current methods (invasive muscle biopsies) to assess cell survival, differentiation and function over time. Reporter gene imaging represents a powerful approach to study the physiology and biology of transplanted cells in vivo. Our strategy is to use cells harvested from a transgenic mouse line that harbors a unified fusion reporter gene composed of different genes whose expression can be imaged with different imaging modalities, in both individual cells and living subjects. This approach allows us to merge PET and optical imaging techniques for applications in a single living subject, and should facilitate rapid translation of approaches developed in cells to preclinical models and to clinical applications. PET is particularly well-suited for translational research, and thus forms the basis of our future research.

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder that affects 1 in 3500 boys, and is characterized by muscle degeneration; patients are confined to a wheelchair when young and succumb to the disease in their 2nd-3rd decade of life. To date, an effective treatment is lacking. Stem cell therapy is a good candidate for treatment since healthy myogenic (muscle-forming) cells can be transplanted to damaged muscle. A limitation to cell therapy, however, is the poor ability of transplanted cells to migrate and engraft within damaged muscle. Therefore, The Duchenne Research Initiative (Lawson) is developing methods to address this issue, in both skeletal and cardiac muscle tissues. One such approach is, for the first time, to adapt a Bioelectromagnetics model to help overcome a great limitation in DMD research and translation; in brief, we propose to use specific magnetic fields to direct the migration of cells following transplant into damaged muscle.

L. Hoffman
molecular imaging, DMD
S. Dhanvantari
molecular imaging, DMD/diabetes
T.-Y. Lee
M.S. Kovacs
PET radiochemistry
A.W. Thomas
bioelectromagnetics, DMD
F.S. Prato
bioelectromagnetics, imaging physics
Cyclotron & PET Radiochemistry
Molecular Imaging

D. Hill
stem cell therapy for DMD, diabetes
Key Accomplishments

Our group has the ability to track myogenic cells as they differentiate in vivo. Specifically, our group has generated a transgenic mouse line that harbors a PET reporter gene, sr39tk, under the control of a well-characterized, muscle-specific myogenin promoter. The promoter is activated only upon differentiation of activated muscle satellite stem cells (SCs). SCs harvested from these mice have been implanted into the calf muscle of a dystrophic (mdx) mouse model of DMD. Four weeks post-implant, we can detect the presence of tk-expressing myoblasts in the mouse. Our group has also developed in vivo functional imaging techniques using dynamic contrast enhanced computed tomography (DCE-CT), PET-FDG scanning and high frequency 3D ultrasound (HFU) to assess changes over time in muscle perfusion, metabolism and morphology, respectively, in 2 mouse models of DMD. These studies clearly demonstrate that non-invasive imaging of biomarkers correlates well with conventional histological analyses of DMD, accurately reflects the severity of the disease state, and can be potentially translated to the clinic as an alternative to invasive procedures. We will now use these imaging techniques to assess the regenerative capacity of transgenic SCs following transplant into dystrophic mice.

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